The aim of this study was to compare the effects of an inhibitor of sorbitol dehydrogenase (2-hydroxyl-methyl-4-(N,N-dimethylsulfamoyl-piperazino)pyrimidine=CP-166 572=SDI),200mg/kg bwt/day, versus an inhibitor of aldose reductase (zopolrestat=ARI), 100mg/kg bwt/day, on tibial motor nerve conduction velocity (MNCV) in rats with streptozotocin (55 mg/kg bwt) diabetes of 14 weeks duration. Plasma glucose levels were 5.5+/- 0.9(SD) mM in control (C) rats versus 24+/-4.2mM in diabetics (D) and were unaffected by SDI or ARI. MNCV was 62.6+/-5.1 m/s in C, 68.0+/-5.6 in C+SDI, 50.4+/-3.4 in D, 66.7+/5.9 in D+SDI, and 59.4+/-7.4 in D+ARI. In rats with diabetes of 5 weeks duration sciatic nerve sorbitol, myo-inositol, and fructose levels were 1863+/-623, 2875+/-737, and 5815+/-1711 versus 159+/-55, 4148+/-1693, and 814+/-197 for C, 2050+/-697, 4351+/-1290, and 425+/-201 for C+SDI, 9975+/-4397, 2844+/-793, and 1001+/-519 for D+SDI, and 170+/-3521+/-1299, and 1217+/-253 for D+ARI. In this same study, SDI and ARI prevented increased sciatic nerve blood flow in D but had no effect in C. These findings indicate that MNCV and vascular dysfunction in peripheral nerve of acutely diabetic rats are more closely linked to metabolic and redox imbalances associated with increased oxidation of sorbitol to fructose than to reduction of glucose to sorbitol, putative osmotic effects of elevated sorbitol levels, and decreased myo-inositol levels.